Allylic sulfones containing triene moieties as key synthons for carotenoid synthesis

Article abstract of DOI:10.1002/hlca.200390211

An efficient synthetic method for the allylic sulfone 2 containing a conjugated triene moiety has been proposed involving i) coupling of allylic sulfones 4 with the C5 bromoallylic sulfide 5, ii) base-promoted dehydrosulfonation in the presence of allylic sulfide, and iii) selective oxidation of the resulting trienyl sulfide to the corresponding sulfone. Total synthesis of lycopene starting from the C₁₅ allylic sulfone 2b has been described, where the new C₁₀ bis(chloroallylic) sulfone 11 proved to be a useful substitute for the C₁₀ bis(chloroallylic) sulfide 3, which did not require the problematic chemoselective sulfur oxidation in a conjugated polyene.

Full text of DOI:10.1002/hlca.200390211

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Helvetica Chimica Acta Vol. 86 (2003)
Allylic Sulfones Containing Triene Moieties as Key Synthons for Carotenoid
Synthesis
by Minkoo Jia), Hojin Choia), Young Cheol Jeonga), Jingquan Jina), Woonphil Baika), Sijoon Leeb),
Jeong Soo Kimb), Minsoo Parkb), and Sangho Koo*a)
a) Department of Chemistry, Myong Ji University, Yongin, Kyunggi-Do, 449-728, Korea
(e-mail: sangkoo@mju.ac.kr)
b) Chemical Research Center, SK Corporation, 140-1, Wonchon-Dong, Yusung-Gu, Taejon, 305-370, Korea
An efficient synthetic method for the allylic sulfone 2 containing a conjugated triene moiety has been
proposed involving i) coupling of allylic sulfones 4 with the C5 bromoallylic sulfide 5, ii) base-promoted
dehydrosulfonation in the presence of allylic sulfide, and iii) selective oxidation of the resulting trienyl sulfide to
the corresponding sulfone. Total synthesis of lycopene starting from the C15 allylic sulfone 2b has been described,
where the new C10 bis(chloroallylic) sulfone 11 proved to be a useful substitute for the C10 bis(chloroallylic)
sulfide 3, which did not require the problematic chemoselective sulfur oxidation in a conjugated polyene.
Introduction.
Carotenoids such as b-carotene (1a) and lycopene (1b) are
characterized by long conjugated polyene chains that show distinctive red colors and
are ideally utilized as nonhazardous dyes for foodstuffs. High reactivity of these
polyenes with activated carcinogenic oxygen or radicals provides carotenoids with
prophylactic effects against certain cancers of the pancreas, the mouth, and the bladder,
etc. [1]. Among the numerous approaches that have appeared in the literature to build
the conjugated polyene chains of carotenoids [2], methods based on acetylide coupling/
partial hydrogenation [3] and Wittig olefination [4] have been the two main synthetic
approaches. The Julia sulfone olefination protocol [5], which has been applied to
retinol synthesis [6], is presumed to be the best method to produce double bonds with
the (E)-configuration [7]. We have introduced the C10 bis(chloroallylic) sulfide 3 as a
stable substitute for the highly unstable 1,8-dichloro-2,7-dimethylocta-2,4,6-triene, and
successfully accomplished total syntheses of b-carotene (1a) and lycopene (1b) based
on the Julia sulfone-olefination protocol [8]. To generalize this process with C10
bis(chloroallylic) sulfide 3 for carotenoid syntheses, an efficient method should be
devised to build allylic sulfones containing conjugated CˆC bonds such as 2
(Scheme 1). We herein report our strategy to synthesize allylic sulfones comprising a
conjugated triene moiety and total synthesis of lycopene [9] by means of the allylic
sulfone 2b.
Results and Discussion. The number of C-atoms in carotenoids is generally a
multiple of 5 due to the biogenetic origin [2][10], and, thus, we started the synthetic
procedure for allylic sulfones 2 from C10 cyclogeranyl [11], geranyl, and C5 prenyl
sulfones 4a, 4b, and 4c, respectively (Scheme 2 and Table). The coupling reaction of the
anions of the allylic sulfones 4a 4c with our chain-extending C5 unit 5 [8b] produced

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Scheme 1. Retro Synthesis of Carotenoids by Utilization of Sulfur Chemistry
the chain-extended allylic sulfides 6a 6c. The anion-stabilizing ability of sulfone is far
superior to that of sulfide, and, therefore, no proton exchange occurred during their
coupling reactions with the bromoallylic sulfide 5 to give excellent yields of the
coupling products. It is also this difference in anion-stabilizing ability that makes
sulfone a better leaving group than sulfide, and, thus, chemoselective base-promoted
dehydrosulfonation reactions of 6 proceeded to bring two isolated CˆC bonds into
conjugation, producing the allylic sulfides 7a 7c with a conjugated triene moiety.
Chemoselective oxidation of sulfur was then accomplished by the LiNbMoO6ÀH2O2
oxidant system [12], without any oxidation of the CˆC bonds, to produce the desired
allylic sulfones 2a 2c containing conjugated triene moieties.
Table. Yields and Stereoisomer Ratios of the Reaction Products 6, 7, and 2 (see Scheme 2) and UV Absorption
Values of (all-E)-2 in CHCl3
4
6 ((E)/(Z))
7 ((2E)/(2Z))
2 ((2E)/(2Z))
UV [lmax (emax)]
of (all-E)-2
93% (4 : 1)
80% (3 : 1)
93% (3 : 1)
279 nm (15,590)
93% (4 : 1)
95% (5 : 1)
75% (2.5 : 1)
78% (3 : 1)
77% (2.5 : 1)
73% (3 : 1)
294 nm (13,235)
291 nm (7,978)
The Table summarizes the yields and the stereoisomer ratios of the products in the
above reaction sequence and UV absorption characteristics of the allylic sulfones 2a
2c containing conjugated (all-E)-triene moieties. The stereoisomer ratios of the CˆC
bond in 6 reflect those of the C5 bromoallylic sulfide 5, which was generated in a 4 5 :1
(E)/(Z) ratio [8b]. It is believed that there is no stereoisomerization during the

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 2. Synthesis of the Allylic Sulfones 2 Containing a Conjugated Triene Moiety
a) 1) BuLi in THF at À788; 2 )5 at À788 to r.t. b) NaOEt in refluxing EtOH. c) LiNbMoO6 (0.05 equiv.) and
H2O2 (2.5 equiv.) in MeOH at 08 to r.t.
coupling reaction between 4 and 5 under the above reaction conditions. Base-promoted
dehydrosulfonation of 6 requires anti-disposition of one of the H-atoms at C(4) and the
PhSO2 group at C(5), which is tentatively depicted for 6b in Scheme 3. The
conformation of 6b is based on the coupling constants of the Ha-atom to the PhSO2
1
group in the H-NMR spectrum, which are 11.5, 10.4, and 3.0 Hz. These values are
typical for strain-free acyclic sulfones. Two vicinal coupling constants with diaster-
eotopic sp3-hybridized H-atoms at C(4) are 11.5 and 3.0 Hz, which indicate dihedral
angles of ca. 1808 and ca. 608, respectively, according to the Karplus correlation [13].
Base-promoted anti-elimination of the H-atom and the PhSO2 group then produced the
(E)-CˆC bond at C(4) in conjugation with the other two CˆC bonds [7]. The (E)/(Z)
stereoisomer ratios of the CˆC bond at C(2) in 7, however, deteriorated during this
elimination process presumably due to an allylic migration of the anion at C(4), which
might be formed under the harsh conditions in boiling EtOH. This indicated that the
elimination process proceeded by an E1cb-like E2 mechanism. These stereoisomers of
the allylic sulfide 7 were not separable. However, the corresponding sulfones 2 can be
separated and unambiguously identified as (E)- and (Z)-isomers at C(2) by NOE
experiments.
Scheme 3. The Conformation of 6b and the Course of Base-Promoted Dehydrosulfonation Reaction
Since the allylic sulfone 2a has been successfully applied to b-carotene synthesis
[8a], we wanted to show the generality of our carotenoid synthesis utilizing C10
bis(chloroallylic) sulfide 3 in the lycopene synthesis, starting from the allylic sulfone
2b containing the (all-E)-triene (Scheme 4). Deprotonation of 2b with NaH in THF,

Helvetica Chimica Acta Vol. 86 (2003)
2623
followed by the coupling reaction with 0.5 equiv of 3 at both termini, produced the C40
coupling product 8 in 90% yield with the required C-skeleton for lycopene synthesis.
Chemoselective sulfur oxidation of 8 to 9, however, was problematic due to the
presence of the conjugated CˆC bonds, probably leading to various oxidation products.
The best yield of 40% was obtained by the oxidation with monoperphthalic acid that
was generated in situ by the reaction of phthalic anhydride and a ureaÀH2O2 complex
in Me3CN [14].
Scheme 4. Synthesis of Lycopene Starting from the Allylic Sulfone 2b
a) 1) NaH in THF at 08; 2 )3 (0.5 equiv.) at 08; 3) NaI at 08 to r.t.; 90%. b) Urea-H2O2 (5 equiv.) and phthalic
anhydride (2.5 equiv.) in MeCN at 08; 40%. c) LiNbMoO6 (0.05 equiv.) and H2O2 (4 equiv.) in MeOH; 71%. d)
t
t
1) BuOK in DMF at À208; 2 )11 (0.5 equiv.) at À208; 86%. e) KOH in BuOH and CCl4; 63%. f) EtONa in
refluxing EtOH; 78%.
At this point, the possibility of utilizing the new C10 bis(chloroallylic) sulfone 11 in
the coupling reaction with the allylic sulfone 2b to directly produce the C40 bis(allylic)
sulfone 9 has been studied in order to avoid the problematic sulfur oxidation reaction of
8 to 9. The C10 bis(chloroallylic) sulfone 11 can be obtained in 71% yield from the C10
bis(chloroallylic) sulfide 3 by chemoselective sulfur oxidation with H2O2 under

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Helvetica Chimica Acta Vol. 86 (2003)
LiNbMoO6 catalyst. The choice of deprotonating base and solvent is crucial in the
coupling reaction of the allylic sulfone 2b and the allylic chloride 11. The use of NaH or
BuLi in THF produced an appreciable amount of the dehydrochlorination product
from the bis(chloroallylic) sulfone 11. The coupling reaction of 2b and 11, on the other
t
hand, proceeded efficiently with BuOK as a base in DMF to produce the coupling
product 9 in 86% yield.
The RambergÀB‰cklund reaction of the bisallylic sulfone 9 under Meyer×s
conditions [15] at ambient temperature produced compound 10 containing the central
conjugated triene moiety in 63% yield. The presence of a small amount (less than 10%)
of a stereoisomer of compound 10, presumably the (15Z)-isomer, was also observed in
1H-NMR spectrum. Compound 10 is unstable under air especially in solution, and it
must be handled and stored under inert atmosphere. EtONa-Promoted dehydrosulfo-
nation of 10 in refluxing EtOH produced lycopene (1b) in 78% yield under the
condition where thermal isomerization to (all-E)-double bonds occurred.
In conclusion, we have developed an efficient synthetic method of allylic sulfones
containing a conjugated triene. The allylic sulfone 2a has previously been efficiently
used for the syntheses of retinal [6], retinoic acid [6a], and b-carotene [8a]. We also
demonstrated the total synthesis of lycopene (1b) by means of the allylic sulfone 2b,
where the new C10 bis(chloroallylic) sulfone 11 was proved to be a useful substitute for
the C10 bis(chloroallylic) sulfide 3. Furthermore, these allylic sulfones may well be
applied to the synthesis of conducting organic compounds containing fully conjugated
polyene chains.
Experimental Part
General. Solvents used as reaction media were dried over molecular sieves (5 ä) pre-dried in a microwave
oven. All reactions were performed under dry Ar in oven-dried glassware, except for those reactions with H2O
as a solvent, which were run in air. Solvents for extraction and chromatography were reagent-grade and were
1
used as received. Column chromatography (CC): silica gel 60, 230 400 mesh ASTM supplied by Merck. H-
(300 MHz) and 13C-NMR (75.5 MHz) spectra: in CDCl3 with Me4Si (d ˆ 0 ppm) as an internal standard.
3-Methyl-1-(phenylsulfanyl)-5-(phenylsulfonyl)-5-(2,6,6-trimethylcyclohex-1-enyl)pent-2-ene (6a). To a
stirred soln. of b-cyclogeranyl phenyl sulfone (4a) (2.06 g, 7.40 mmol) in THF (30 ml) at À788 was slowly
added 1.6m soln. of BuLi in hexane (5.1 ml, 8.14 mmol). The mixture was stirred at that temp. for 30 min and
then treated with a soln. of 4-bromo-3-methylbut-2-enyl phenyl sulfide (5) [8b] (2.31 g, 9.00 mmol, 4 :1 (E)/(Z))
in THF. The mixture was slowly warmed and stirred at r.t. for 14 h, diluted with Et2O, washed with 1m HCl soln.
and water, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified
by SiO2 flash column chromatography to give 6a (3.14 g, 6.90 mmol) in 93% yield. The (2E)/(2Z) ratio of 4 :1
1
was based on H-NMR analysis.
Data of (2E)-6a: IR (neat) 1446, 1304, 1143. 1H-NMR: 0.81 (s, 3 H); 1.05 (s, 3 H); 1.2 4 (s, 3 H); 1.33 1.77
(m, 4 H); 1.90 2.20 (m, 2H); 2.00 ( s, 3 H); 2.62 (d of A of ABq, JAB ˆ 14.5, Jd ˆ 6.4, 1 H); 3.00 (d of B of ABq,
JAB ˆ 14.5, Jd ˆ 6.6, 1 H); 3.40 (dd, J ˆ 7.6, 2.7, 2 H); 3.90 (dd, J ˆ 6.6, 6.4, 1 H); 5.35 (t, J ˆ 7.6, 1 H); 7.15 7.33
(m, 5 H); 7.43 7.65 (m, 3 H); 7.80 7.96 (m, 2 H). 13C-NMR: 15.4; 18.9; 23.3; 28.4; 29.1; 31.9; 34.5; 35.9; 39.6;
40.9; 65.4; 123.8; 126.1; 128.3; 128.7; 128.7; 129.5; 130.0; 130.5; 133.0; 134.9; 137.9; 141.9. CI-HR-MS (pos.):
‡
455.2087 (C27H35O2S2 ; calc. 455.2079).
3,7,11-Trimethyl-1-(phenylsulfanyl)-5-(phenylsulfonyl)dodeca-2,6,10-triene (6b) [8b]. According to the
general procedure for 6a, geranyl phenyl sulfone (4b; 28.7 g, 103 mmol) in THF (150 ml) at 08 was deprotonated
with a 1.6m soln. of BuLi in hexane (64 ml, 103 mmol), and then reacted with 5 (29.1 g, 113 mmol; (E)/(Z) 4 :1)
1
for 11 h at r.t. to give 6b (43.6 g, 96 mmol) in 93% yield. The (2E)/(2Z) ratio of 4 :1 was based on H-NMR
analysis.

Helvetica Chimica Acta Vol. 86 (2003)
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3,7-Dimethyl-1-(phenylsulfanyl)-5-(phenylsulfonyl)octa-2,6-diene (6c) [8b]. According to the general
procedure for 6a, phenyl prenyl sulfone (4c, 14.72g, 70.0 mmol) in THF (70 ml) at À788 was deprotonated with
1.6m soln. of BuLi in hexane (45.9 ml, 73.5 mmol), and then reacted with 5 (18.0 g, 70.0 mmol; (E)/(Z) 5 :1) for
1
2 h at À788 to give 6c (25.58 g, 66.2 mmol) in 95% yield. The (2E)/(2Z) ratio of 5 :1 was based on H-NMR
analysis.
3-Methyl-1-(phenylsulfanyl)-5-(2,6,6-trimethylcyclohex-1-enyl)penta-2,4-diene (7a). Na (1.19 g, 51.7 mmol)
was added to anh. EtOH (30 ml) at 08. The mixture was then heated to reflux for 1 h and cooled to r.t. A soln. of
6a (2.35 g, 5.17 mmol) in EtOH (5 ml) was added, and the mixture was heated to reflux for 10 h. Upon cooling to
r.t., the reaction was quenched with H2O, and the mixture was extracted with hexanes, dried (Na2SO4), filtered,
and concentrated under reduced pressure. The crude product was purified by SiO2 flash column chromatog-
raphy to give 7a (1.30 g, 4.15 mmol) in 80% yield, which was composed of a 3 :1 mixture of stereoisomers
according to 1H-NMR analysis. These isomers were inseparable by CC; however, they were separated after
oxidation to sulfones 2a in the next step and unambiguously identified as (2E)- and (2Z)-isomers, respectively,
by NOE experiments.
Data of (2Z)-7a: 1H-NMR: 1.01 (s, 6 H); 1.42 1.48 ( m, 2H); 1.56 1.64 ( m, 2H); 1.69 ( s, 3 H); 1.88 (s,
3 H); 1.99 (t, J ˆ 5.7, 2H); 3.71 ( d, J ˆ 8.0, 2H); 5.44 ( t, J ˆ 8.0, 1 H); 6.27 (A of ABq, J ˆ 16.2, 1 H); 6.37 (B of
ABq, J ˆ 16.2Hz, 1 H); 7.13 7.27 ( m, 3 H); 7.27 7.38 (m, 2 H). 13C-NMR: 12.5; 19.2; 19.8; 21.7; 28.9; 31.3; 32.9;
34.1; 39.5; 117.8; 125.9; 126.2; 126.4; 128.9; 129.1; 130.4; 136.2; 137.9; 139.0.
Data of (all-E)-7a: IR (neat): 1477, 1440, 966. 1H-NMR: 0.99 (s, 6 H); 1.42 1.48 ( m, 2H); 1.56 1.64 ( m,
2H); 1.67 ( s, 3 H); 1.70 (s, 3 H); 1.99 (t, J ˆ 5.7, 2H); 3.68 ( d, J ˆ 7.9, 2H); 5.53 ( t, J ˆ 7.9, 1 H); 6.02(br. s, 2 H);
7.13 7.27 (m, 3 H); 7.27 7.38 (m, 2 H). 13C-NMR: 12.1; 19.2; 19.8; 21.6; 28.9; 32.8; 32.9; 34.2; 39.5; 112.9; 124.5;
‡
126.3; 126.5; 128.7; 129.3; 130.4; 136.9; 137.5; 137.6. CI-HR-MS (pos.): 313.1999 (C21H29S ; calc. 313.1990).
3,7,11-Trimethyl-1-(phenylsulfanyl)dodeca-2,4,6,10-tetraene (7b). According to the general procedure for
7a, EtONa, prepared by reacting Na (15.5 g, 0.673 mol) with anh. EtOH (160 ml), was reacted with 6b (15.3 g,
33.7 mmol) to give 7b (7.92 g, 25.3 mmol) in 75% yield, composed of a 2.5 :1 mixture of stereoisomers according
to 1H-NMR analysis. These isomers were inseparable by CC; however, they were separated after oxidation to
sulfones 2b in the next step and unambiguously identified as (2E)- and (2Z)-isomers, respectively, by NOE
experiments.
Data of (2Z)-7b: 1H-NMR: 1.60 (s, 3 H); 1.68 (s, 3 H); 1.79 (s, 3 H); 1.88 (s, 3 H); 2.10 (br. s, 4 H); 3.73 (d,
J ˆ 7.9, 2H); 5.10 (br. s, 1 H); 5.44 (t, J ˆ 7.9, 1 H); 5.93 (d, J ˆ 11.5, 1 H); 6.16 (d, J ˆ 15.2, 1 H); 6.47 (dd, J ˆ
15.2, 11.0, 1 H); 7.12 7.44 (m, 5 H). 13C-NMR: 12.3; 16.9; 20.4; 25.7; 26.6; 31.3; 40.1; 123.1; 123.9; 126.0; 126.3;
127.1; 128.8; 129.4; 130.3; 131.8; 136.2; 136.3; 140.5 ppm.
Data of (all-E)-7b: IR (neat): 1480, 1440, 1378. 1H-NMR: 1.60 (s, 3 H); 1.68 (s, 3 H); 1.71 (s, 3 H); 1.78 (s,
3 H); 2.09 (br. s, 4 H); 3.67 (d, J ˆ 8.0, 2H); 5.10 (br. s, 1 H); 5.57 (t, J ˆ 8.0, 1 H); 5.89 (d, J ˆ 11.0, 1 H); 6.16 (d,
J ˆ 15.2, 1 H); 6.40 (dd, J ˆ 15.2, 11.0, 1 H); 7.12 7.44 (m, 5 H). 13C-NMR: 12.3; 16.8; 17.7; 25.7; 26.6; 32.8; 40.1;
123.9; 124.7; 125.1; 125.4; 126.3; 128.8; 129.4; 130.3; 131.7; 134.4; 137.5; 139.4. CI-HR-MS (pos.): 313.1988
‡
(C21H29S ; calc. 313.1990).
3,7-Dimethyl-1-(phenylsulfanyl)octa-2,4,6-triene (7c). According to the general procedure for 7a, EtONa,
prepared by reacting Na (0.612g, 26.6 mol) with anh. EtOH (30 ml), was reacted with 6c (1.03 g, 2.66 mmol) to
1
give 7c (0.507 g, 2.08 mmol) in 78% yield, composed of a 3 :1 mixture of stereoisomers according to H-NMR
analysis. These isomers were inseparable by CC; however, they were separated after oxidation to sulfones 2c in
the next step and unambiguously identified as (2E)- and (2Z)-isomers, respectively, by NOE experiments.
Data of (2Z)-7c: 1H-NMR: 1.81 (s, 3 H); 1.86 (s, 3 H); 3.72( d, J ˆ 7.5, 2H); 5.43 ( t, J ˆ 7.5, 1 H); 5.91 (d, J ˆ
9.3, 1 H); 6.46 (dd, J ˆ 11.1, 9.3, 1 H). 13C-NMR: 18.5; 20.4; 26.2; 31.3; 123.0; 125.8; 125.9; 127.1; 129.3; 136.3;
136.7; 137.9.
Data of (2-E)-7c: IR (neat): 1480, 1439. 1H-NMR: 1.71 (s, 3 H); 1.78 (s, 3 H); 1.80 (s, 3 H); 3.67 (d, J ˆ 8.1,
2H); 5.56 ( t, J ˆ 7.9, 1 H); 5.86 (d, J ˆ 10.7, 1 H); 6.12( d, J ˆ 15.4, 1 H); 6.37 (dd, J ˆ 15.4, 10.7, 1 H); 7.15 7.40
(m, 5 H). 13C-NMR: 12.3; 18.5; 26.2; 32.8; 124.7; 125.3; 125.5; 126.3; 128.8; 130.3; 133.9; 135.8; 136.2; 137.5. CI-
‡
HR-MS (pos.): 245.1370 (C16H21S ; calc. 245.1364).
3-Methyl-1-(phenylsulfonyl)-5-(2,6,6-trimethylcyclohex-1-enyl)penta-2,4-diene (2a) [6b]. To a stirred soln.
of 7a (1.30 g, 4.15 mmol) in MeOH (10 ml) and benzene (5 ml) were added LiNbMoO6 (26.3 mg, 0.09 mmol)
and 30% aq. H2O2 soln. (2.78 g, 8.58 mmol) consecutively at 08. After the mixture was slowly warmed and stirred
at r.t. for 6 h, it was concentrated under reduced pressure. The crude mixture was dissolved in CHCl3, washed
with H2O, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified
by SiO2 flash column chromatography to give (2Z)-2a (0.33 g, 0.96 mmol) and (all-E)-2a (0.99 g, 2.88 mmol) in
23 and 70% yields, resp.

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3,7,11-Trimethyl-1-(phenylsulfonyl)dodeca-2,4,6,10-tetraene (2b) [12]. According to the general procedure
for 2a, a soln. of 7b (16.1 g, 51.5 mmol) in benzene (30 ml) and MeOH (70 ml) was reacted with LiNbMoO6
(301 mg, 1.03 mmol) and 35% aq. H2O2 soln. (12.5 g, 0.129 mol) at r.t. for 6 h to give (2Z)-2b (3.91 g, 11.4 mmol)
and (all-E)-2b (9.79 g, 28.4 mmol) in 22 and 55% yields, resp.
3,7-Dimethyl-1-(phenylsulfonyl)octa-2,4,6-triene (2c) [16]. According to the general procedure for 2a, a
soln. of 7c (0.42g, 1.73 mmol) in MeOH (20 ml) was reacted with LiNbMoO 6 (25 mg, 0.09 mmol) and 30% aq.
H2O2 soln. (0.65 g, 5.71 mmol) at r.t. for 6 h to give (2Z)-2c (87 mg, 0.31 mmol) and (all-E)-2c (262 mg,
0.95 mmol) in 18 and 55% yields, resp.
Bis[3,7,11,15-tetramethyl-5-(phenylsulfonyl)hexadeca-2,6,8,10,14-pentaenyl] Sulfide (8). To a stirred soln.
of 2b (7.29 g, 21.2 mmol) in THF (50 ml) at 08 was added 60% NaH (1.02g, 25.4 mmol). The mixture was stirred
for 30 min, and then bis(chloroallylic) sulfide 3 (2.53 g, 10.6 mmol) and NaI (3.81 g, 25.4 mmol) were added
consecutively. The mixture was stirred at r.t. for 15 h, diluted with Et2O, washed with 1m HCl and H2O, dried
(Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 flash
column chromatography to give 8 (8.15 g, 9.53 mmol) in 90% yield. IR (neat): 1447, 1304, 1146, 1084. 1H-NMR:
1.29 (s, 6 H); 1.50 (s, 6 H); 1.61 (s, 6 H); 1.69 (s, 6 H); 1.76 (s, 6 H); 2.10 (br. s, 8 H); 2.34 (dd, J ˆ 13.0, 11.7, 2H);
2.91 (d, J ˆ 7.5, 4 H); 2.75 3.18 (m, 2H); 4.00 ( dd, J ˆ 10.3, 9.2, 2 H); 5.09 (br. s, 4 H); 5.19 (t, J ˆ 7.5, 2H); 5.85
(d, J ˆ 10.6, 2H); 6.06 ( d, J ˆ 15.2, 2 H); 6.30 (dd, J ˆ 15.2, 10.6, 2 H); 7.43 7.55 (m, 4 H); 7.55 7.66 (m, 2 H);
7.73 7.86 (m, 4 H). 13C-NMR: 12.5; 15.9; 16.9; 17.7; 25.7; 26.5; 28.1; 37.5; 40.1; 63.8; 110.0; 121.8; 123.8; 124.7;
‡
124.8; 126.2; 128.8; 129.1; 131.7; 133.2; 133.5; 137.7; 140.9; 142.2. FAB-HR-MS (pos.): 713.4446 (C46H65O2S2 ,
‡
[C52H71O4S3 C6H6O2S] ; calc. 713.4426).
Bis[3,7,11,15-tetramethyl-5-(phenylsulfonyl)hexadeca-2,6,8,10,14-pentaenyl) Sulfone (9). Method A (Oxi-
dation of 8). The mixture of ureaÀH2O2 (UHP; 3.42g, 36.4 mmol) and phthalic anhydride (2.70 g, 18.2mmol)
in MeCN (50 ml) were stirred vigorously at r.t. to give a clear soln. This soln. was slowly added with a dropper to
a soln. of 8 (6.23 g, 7.28 mmol) in MeCN (50 ml) at 08 for 3 h. The mixture was stirred for another 2h and, the
reaction was quenched with 1m HCl soln. This mixture was extracted with AcOEt, dried (Na2SO4), filtered, and
concentrated under reduced pressure to give a white solid, which was then dissolved in CHCl3. The insoluble
solid material was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude
product was purified by SiO2 flash column chromatography to give 9 (2.58 g, 2.91 mmol) in 40% yield.
Method B (Coupling of 2b and 11). To a stirred soln. of 2b (4.29 g, 12.45 mmol) in DMF (25 ml) at À208
under Ar was added tBuOK (1.62g, 13.7 mmol) in several portions. The mixture was stirred for 30 min at that
temp., and a soln. of bis(allylic) sulfone 11 (1.69 g, 6.22 mmol) in DMF (10 ml) was added slowly for 2 h. Stirring
the mixture for 1 h at À208, 1m HCl (100 ml) and AcOEt (70 ml) were added. The org. layer was separated,
washed with sat. NaHCO3 soln. and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure.
The crude product was purified by SiO2 flash column chromatography to give 9 (4.77 g, 5.38 mmol) in 86% yield.
IR (neat): 1447, 1305, 1146, 1084. 1H-NMR: 1.29 (s, 6 H); 1.61 (s, 6 H); 1.62( s, 6 H); 1.69 (s, 6 H); 1.75 (s, 6 H);
2.09 (br. s, 8 H); 2 .43 (dd, J ˆ 13.5, 11.2, 2 H); 3.02 (br. d, J ˆ 13.5, 2H); 3.48 ( d, J ˆ 7.4, 4 H); 4.04 (ddd, J ˆ 11.2,
9.7, 3.1, 2H); 5.08 ( d, J ˆ 9.7, 2H); 5.10 (br. s, 2 H); 5.23 (t, J ˆ 7.4, 2H); 5.85 ( d, J ˆ 10.9, 2H); 6.05 ( d, J ˆ 15.2,
2H); 6.33 ( dd, J ˆ 15.2, 10.9, 2 H); 7.45 7.57 (m, 4 H); 7.57 7.68 (m, 2H); 7.74 7.85 ( m, 4 H). 13C-NMR: 12.5;
16.9; 17.0; 17.7; 25.7; 26.6; 37.7; 40.1; 51.3; 63.5; 114.1; 121.2; 123.7; 124.7; 126.8; 128.9; 129.2; 131.9; 132.8; 133.7;
‡
‡
‡
137.3; 140.9; 141.5; 142.7. FAB -HR-MS: 603.4240 (C40H59O2S , [C52H71O6S3 2 C6H6O2S] ; calc. 603.4236).
Bis(4-chloro-3-methylbut-2-enyl) Sulfone (11). According to the general procedure for 2a, a soln. of 3
(1.00 g, 4.18 mmol) in MeOH (20 ml) was reacted with LiNbMoO6 (60 mg, 0.21 mmol) and 35% aq. H2O2 soln.
(1.62g, 16.72mmol) at r.t. for 3 h to give 11 (0.80 g, 2.95 mmol) in 71% yield. IR (neat): 1444, 1307, 1117.
1H-NMR: 1.86 (s, 6 H); 3.74 (d, J ˆ 7.7, 4 H); 4.07 (s, 4 H); 5.69 (t, J ˆ 7.7, 2H ) . 13C-NMR: 15.0; 50.1; 51.9; 115.2;
141.5. Anal. calc. for C10H16Cl2O2S: C 44.29, H 5.95, S 11.82; found: C 44.25, H 5.99, S 11.76.
11,11',12,12'-Tetrahydro-11,11'-bis(phenylsulfonyl)lycopene (10). To a soln. of 9 (627 mg, 0.71 mmol) in
tBuOH (15 ml) and CCl4 (15 ml) was added pulverized KOH (793 mg, 14.1 mmol) at r.t. under Ar. This mixture
was stirred vigorously for 7 h at that temp., diluted with CH2Cl2, washed with 1m HCl soln. and H2O, dried
(Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 flash
column chromatography to give 10 (367 mg, 0.48 mmol) in 63% yield, which contained a small amount (ca.
10%) of a stereoisomer, presumably the (15Z)-isomer. This compound is very unstable in air, and the actual
1
yield should be higher than that sited above. IR (neat): 1448, 1305, 1147, 1085. H-NMR: 1.28 (s, 6 H); 1.60 (s,
6 H); 1.65 (s, 6 H); 1.68 (s, 6 H); 1.74 (s, 6 H); 2.08 (br. s, 8 H); 2.41 (dd, J ˆ 13.2, 11.8, 2 H); 3.03 (d, J ˆ 13.2,
2H); 4.04 ( ddd, J ˆ 11.8, 9.0, 2.1, 2 H); 5.10 (br. s, 4 H); 5.87 (br. s, 4 H); 6.07 (d, J ˆ 15.0, 2H); 6.20 ( m, 2 H);
6.31 (dd, J ˆ 15.0, 10.1, 2H); 7.40 7.70 ( m, 6 H); 7.73 7.88 (m, 4 H). 13C-NMR: 12.4; 16.8; 17.1; 17.6; 25.6; 26.5;
38.1; 40.0; 63.9; 121.7; 123.7; 124.8; 126.1; 127.8; 128.4; 128.8; 129.1; 131.7; 133.0; 133.3; 133.5; 137.6; 140.9; 142.1.

Helvetica Chimica Acta Vol. 86 (2003)
2627
Lycopene (1b) [8b][9c]. According to the general procedure for 7a, EtONa, prepared by reacting Na
(414 mg, 18.0 mol) with anh. EtOH (20 ml), was reacted with 10 (367 mg, 0.45 mmol) in benzene (10 ml) at 908
for 12h to give 1b (188 mg, 0.35 mmol) in 78% yield. The possible (Z)-stereoisomers at C(13), C(13'), C(15),
and C(15') were presumably isomerized to (all-E)-lycopene during this thermolysis reaction. The 1H-NMR
spectrum of the synthetic sample was identical with that of an authentic sample. 1H-NMR: 1.61 (s, 6 H); 1.68 (s,
6 H); 1.82( s, 6 H); 1.96 (s, 12H); 2.11 (br. s, 8 H); 5.11 (br. s, 2H); 5.95 ( d, J ˆ 10.8, 2H); 6.18 ( d, J ˆ 12.1, 2 H);
6.24 (d, J ˆ 14.9, 2H); 6.20 6.30 ( m, 2H); 6.35 ( d, J ˆ 14.8, 2H); 6.49 ( dd, J ˆ 14.9, 10.8, 2H); 6.63 ( dd, J ˆ
14.8, 12.1, 2 H); 6.55 6.70 (m, 2 H).
HPLC Analysis of the synthetic lycopene (1b) was performed on YMC Carotenoid S-5 column (4.6 Â
250 mm) with BuOH/MeCN/CH2Cl2 3 :7:1 as mobile phase (Fig.).
This work was supported by the RRC program of MOST and KOSEF.
Figure. HPLC of the synthetic lycopene (1b) showing mostly (all-E)-lycopene (23.021 min). YMC Carotenoid S-
5 column (4.6 Â 250 mm) with BuOH/MeCN/CH2Cl2 3 :7 :1.
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Received March 14, 2003